Histone deacetylase 9 regulates breast cancer cell proliferation and the response to histone deacetylase inhibitors

Abstract

Histone lysine acetylation is an epigenetic mark regulated by histone acetyltransferases and histone deacetylases (HDAC) which plays an important role in tumorigenesis. In this study, we observed a strong overexpression of class IIa HDAC9, at the mRNA and protein levels, in the most aggressive human breast cancer cell lines (i.e. in basal breast cancer cells vs luminal ones or in malignant vs begnin MCF10A breast epithelial cell lines). HDAC9 overexpression was associated with higher rates of gene transcription and increased epigenetic marks on the HDAC9 promoter. Ectopic expression of HDAC9 in MCF7 luminal breast cancer cells led to an increase in cell proliferation and to a decrease in apoptosis. These effects were associated with a deregulated expression of several genes controlled by HDAC inhibitors such as CDKN1A, BAX and TNFRSF10A. Inversely, knock-down of HDAC9 expression in MDA-MB436 basal breast cancer cells reduced cell proliferation. Moreover, high HDAC9 expression decreased the efficacy of HDAC inhibitors to reduce cell proliferation and to regulate CDKN1A gene expression. Interestingly, the gene encoding the transcription factor SOX9 was identified by a global transcriptomic approach as an HDAC9 target gene. In stably transfected MCF7 cells, SOX9 silencing significantly decreased HDAC9 mitogenic activity. Finally, in a large panel of breast cancer biopsies, HDAC9 expression was significantly increased in tumors of the basal subtype, correlated with SOX9 expression and associated with poor prognosis. Altogether, these results indicate that HDAC9 is a key factor involved in mammary carcinogenesis and in the response to HDAC inhibitors.

Increased expression of the HDAC9 gene is associated with antiestrogen resistance of breast cancers

“…A). Finally, GSEA of microarray data obtained from an independent pool of MCF7 cell clones that overexpress or not HDAC9 (Lapierre et al ., ) confirmed that HDAC9 overexpression led to a significant decrease of genes belonging to the ERα signaling pathway (Fig. B).…”

“…We previously reported that HDAC9 expression was significantly lower in ERα‐positive breast cancer cell lines, such as MCF7 and T47D, compared with ERα‐negative breast cancer cell lines, such as MDA‐MB231 and MDA‐MB436 (Fig. E) (Lapierre et al ., ). Interestingly, the same inverse correlation was found by analyzing several human breast tumor datasets, including the E‐TABM‐158 breast cancer dataset (Chin et al ., ).…”

HDAC9 overexpression confers invasive and angiogenic potential to triple negative breast cancer cells via modulating microRNA-206

“…HDAC9 is thought to regulate gene expression through epigenetic modulation of the chromatin structure by catalyzing the deacetylation of histone proteins [19]. More recently, aberrant HDAC9 expression has been observed in several types of cancers, including medulloblastoma [21], acute lymphoblastic leukemia [22], glioblastoma [23], osteosarcoma [24], and breast cancer [25]. HDAC9 has been shown to promote the growth of these tumors.…”

“…HDAC9 is also known to target non-histone proteins, such as forkhead box protein 3, ataxia telangiectasia group D-complementing protein (ATDC), and glioblastoma 1 protein, which are members of pathways implicated in carcinogenesis [20, 21]. More recently, aberrant HDAC9 expression has been observed in several types of cancers, including medulloblastoma [21], acute lymphoblastic leukemia [22], glioblastoma [23], osteosarcoma [24], and breast cancer [25]. HDAC9 has been shown to promote the growth of these tumors.…”

Divergent JNK Phosphorylation of HDAC3 in Triple-Negative Breast Cancer Cells Determines HDAC Inhibitor Binding and Selectivity

“…However, it remains unclear which isoforms are important to target for efficacy in breast cancer. Correlational studies between individual isoform expression and disease state in breast cancer have been disparate (Lapierre et al, 2016, Zhang et al, 2005b, Muller et al, 2013, Hsieh et al, 2016). In addition to expression, HDAC activity can be regulated through formation of multi-protein complexes and PTM (Zhang et al, 1999, Guenther et al, 2000, Zhang et al, 2005a, Pflum et al, 2001).…”